bims-cagime 2023-06-04 papers

bims-cagime

Biomed News

on Cancer, aging and metabolism

Issue of 2023–06–04
thirty papers selected by
Kıvanç Görgülü, Technical University of Munich

Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.
Tumor heterogeneity: An oncogenic driver of PDAC progression and therapy resistance under stress conditions.
Pancreatic ductal adenocarcinoma ubiquitination profiling reveals specific prognostic and theranostic markers.
Learning consistent subcellular landmarks to quantify changes in multiplexed protein maps.
Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.
Metabolism in the tumour cell and beyond.
In vivo models of pancreatic ductal adenocarcinoma.
Spatially resolved multi-omics single-cell analyses inform mechanisms of immune-dysfunction in pancreatic cancer.
Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis.
Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.
ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.
Immune modulation through secretory autophagy.
An unexpected pathway to polyamines in pancreatic cancer.
Dietary interventions and precision nutrition in cancer therapy.
Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results.
Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.
TGFβ blockade in pancreatic cancer enhances sensitivity to combination chemotherapy.
Circulating tumour cells for early detection of clinically relevant cancer.
Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC)Unveils New Actionable Genomic Aberrations in PACC.
Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer.
AI predicts pancreatic cancer risk.
Inflammatory and alternatively activated macrophages independently induce metaplasia but cooperatively drive pancreatic precancerous lesion growth.
Lipid droplets are a metabolic vulnerability in melanoma.
Senescent alveolar macrophages promote early-stage lung tumorigenesis.
Clinical and translational relevance of intratumor heterogeneity.
In situ tumour arrays reveal early environmental control of cancer immunity.
Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance.
Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.
FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer.

Elife. 2023 May 31. pii: e81289. [Epub ahead of print]12

Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis.

Juan J Apiz Saab, Lindsey N Dzierozynski, Patrick B Jonker, Roya AminiTabrizi, Hardik Shah, Rosa Elena Menjivar, Andrew J Scott, Zeribe C Nwosu, Zhou Zhu, Riona N Chen, Moses Oh, Colin Sheehan, Daniel R Wahl, Marina Pasca di Magliano, Costas A Lyssiotis, Kay F Macleod, Christopher R Weber, Alexander Muir.

  Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors (M. R. Sullivan, Danai, et al., 2019). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.

Keywords:  biochemistry; cancer biology; chemical biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.81289
Adv Cancer Res. 2023 ;pii: S0065-230X(23)00019-2. [Epub ahead of print]159 203-249

Tumor heterogeneity: An oncogenic driver of PDAC progression and therapy resistance under stress conditions.

António M Palma, Vignesh Vudatha, Maria Leonor Peixoto, Esha Madan.

  Pancreatic ductal adenocarcinoma (PDAC) is a clinically challenging disease usually diagnosed at advanced or metastasized stage. By this year end, there are an expected increase in 62,210 new cases and 49,830 deaths in the United States, with 90% corresponding to PDAC subtype alone. Despite advances in cancer therapy, one of the major challenges combating PDAC remains tumor heterogeneity between PDAC patients and within the primary and metastatic lesions of the same patient. This review describes the PDAC subtypes based on the genomic, transcriptional, epigenetic, and metabolic signatures observed among patients and within individual tumors. Recent studies in tumor biology suggest PDAC heterogeneity as a major driver of disease progression under conditions of stress including hypoxia and nutrient deprivation, leading to metabolic reprogramming. We therefore advance our understanding in identifying the underlying mechanisms that interfere with the crosstalk between the extracellular matrix components and tumor cells that define the mechanics of tumor growth and metastasis. The bilateral interaction between the heterogeneous tumor microenvironment and PDAC cells serves as another important contributor that characterizes the tumor-promoting or tumor-suppressing phenotypes providing an opportunity for an effective treatment regime. Furthermore, we highlight the dynamic reciprocating interplay between the stromal and immune cells that impact immune surveillance or immune evasion response and contribute towards a complex process of tumorigenesis. In summary, the review encapsulates the existing knowledge of the currently applied treatments for PDAC with emphasis on tumor heterogeneity, manifesting at multiple levels, impacting disease progression and therapy resistance under stress.

Keywords:  Pancreatic cancer; Resistance; Stress conditions; Therapy; Tumor heterogeneity

DOI:  https://doi.org/10.1016/bs.acr.2023.02.005
EBioMedicine. 2023 May 29. pii: S2352-3964(23)00199-8. [Epub ahead of print]92 104634

Pancreatic ductal adenocarcinoma ubiquitination profiling reveals specific prognostic and theranostic markers.

Abdessamad El Kaoutari, Nicolas A Fraunhoffer, Stéphane Audebert, Luc Camoin, Yolande Berthois, Odile Gayet, Julie Roques, Martin Bigonnet, Claire Bongrain, Joseph Ciccolini, Juan L Iovanna, Nelson J Dusetti, Philippe Soubeyran.

   BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been widely studied at multiomics level. However, little is known about its specific ubiquitination, a major post-translational modification (PTM). As PTMs regulate the final function of any gene, we decided to establish the ubiquitination profiles of 60 PDAC.
METHODS: We used specific proteomic tools to establish the ubiquitin dependent proteome (ubiquitinome) of frozen PDXs (Patients' derived xenographs). Then, we performed bioinformatics analysis to identify the possible associations of these ubiquitination profiles with tumour phenotype, patient survival and resistance to chemotherapies. Finally, we used proximity ligation assays (PLA) to detect and quantify the ubiquitination level of one identified marker.
FINDINGS: We identified 38 ubiquitination site profiles correlating with the transcriptomic phenotype of tumours and four had notable prognostic capabilities. Seventeen ubiquitination profiles displayed potential theranostic marker for gemcitabine, seven for 5-FU, six for oxaliplatin and thirteen for irinotecan. Using PLA, we confirmed the use of one ubiquitination profile as a drug-response marker, directly on paraffin embedded tissues, supporting the possible application of these biomarkers in the clinical setting.
INTERPRETATION: These findings bring new and important insights on the relationship between ubiquitination levels of proteins and different molecular and clinical features of PDAC patients. Markers identified in this study could have a potential application in clinical settings to help to predict response to chemotherapies thereby allowing the personalization of treatments.
FUNDING: Fondation ARC (PJA 20181208270 and PGA 12021010002840_3562); INCa; Canceropôle PACA; DGOS; Amidex Foundation; Fondation de France; and INSERM.

Keywords:  Pancreatic cancer; Ubiquitin profiling; Ubiquitin prognostic markers; Ubiquitin theranostic markers

DOI:  https://doi.org/10.1016/j.ebiom.2023.104634
Nat Methods. 2023 May 29.

Learning consistent subcellular landmarks to quantify changes in multiplexed protein maps.

Hannah Spitzer, Scott Berry, Mark Donoghoe, Lucas Pelkmans, Fabian J Theis.

Highly multiplexed imaging holds enormous promise for understanding how spatial context shapes the activity of the genome and its products at multiple length scales. Here, we introduce a deep learning framework called CAMPA (Conditional Autoencoder for Multiplexed Pixel Analysis), which uses a conditional variational autoencoder to learn representations of molecular pixel profiles that are consistent across heterogeneous cell populations and experimental perturbations. Clustering these pixel-level representations identifies consistent subcellular landmarks, which can be quantitatively compared in terms of their size, shape, molecular composition and relative spatial organization. Using high-resolution multiplexed immunofluorescence, this reveals how subcellular organization changes upon perturbation of RNA synthesis, RNA processing or cell size, and uncovers links between the molecular composition of membraneless organelles and cell-to-cell variability in bulk RNA synthesis rates. By capturing interpretable cellular phenotypes, we anticipate that CAMPA will greatly accelerate the systematic mapping of multiscale atlases of biological organization to identify the rules by which context shapes physiology and disease.

DOI: https://doi.org/10.1038/s41592-023-01894-z
Nat Cancer. 2023 May 29.

Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.

Pravat Kumar Parida, Mauricio Marquez-Palencia, Suvranil Ghosh, Nitin Khandelwal, Kangsan Kim, Vidhya Nair, Xiao-Zheng Liu, Hieu S Vu, Lauren G Zacharias, Paula I Gonzalez-Ericsson, Melinda E Sanders, Bret C Mobley, Jeffrey G McDonald, Andrew Lemoff, Yan Peng, Cheryl Lewis, Gonçalo Vale, Nils Halberg, Carlos L Arteaga, Ariella B Hanker, Ralph J DeBerardinis, Srinivas Malladi.

Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.

DOI: https://doi.org/10.1038/s43018-023-00563-6
Mol Oncol. 2023 May 27.

Metabolism in the tumour cell and beyond.

Arkaitz Carracedo.

  The process of cellular transformation encompasses the acquisition of key and distinctive features, commonly known as hallmarks of cancer. These hallmarks are supported by tumour-intrinsic molecular alterations as well as changes in the microenvironment. Cellular metabolism represents one of the most intimate connections between a cell and the environment. In turn, metabolic adaptation represents a research field of increasing interest in cancer biology. In this viewpoint, I will provide a panoramic perspective of the relevance and repercussions of metabolic alterations in tumours with non-exhaustive illustrative examples and speculate the prospects of cancer metabolism research.

Keywords:  Cancer metabolism; anabolism; metabolic vulnerability; tumor microenvironment

DOI:  https://doi.org/10.1002/1878-0261.13467
Adv Cancer Res. 2023 ;pii: S0065-230X(23)00016-7. [Epub ahead of print]159 75-112

In vivo models of pancreatic ductal adenocarcinoma.

Vignesh Vudatha, Kelly M Herremans, Devon C Freudenberger, Christopher Liu, Jose G Trevino.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with high mortality rate. Within the next decade, PDAC is projected to become the second leading cause of cancer-associated death in the United States. Understanding the pathophysiology of PDAC tumorigenesis and metastases is crucial toward developing new therapeutics. One of the challenges in cancer research is generating in vivo models that closely recapitulate the genomic, histological, and clinical characteristics of human tumors. An ideal model for PDAC not only captures the tumor and stromal environment of human disease, but also allows for mutational control and is easy to reproduce in terms of time and cost. In this review, we highlight evolution of in vivo models for PDAC including spontaneous tumors models (i.e., chemical induction, genetic modification, viral delivery), implantation models including patient derived xenografts (PDX), and humanized PDX. We discuss the implementation of each system and evaluate the benefits and shortcomings of these models. Overall, this review provides a broad overview of prior and current techniques of in vivo PDAC modeling and their associated challenges.

Keywords:  CRISPR; Genetically engineered mouse models; In vivo models; Pancreatic ductal adenocarcinoma; Patient derived xenograft

DOI:  https://doi.org/10.1016/bs.acr.2023.02.002
Gastroenterology. 2023 May 30. pii: S0016-5085(23)00810-7. [Epub ahead of print]

Spatially resolved multi-omics single-cell analyses inform mechanisms of immune-dysfunction in pancreatic cancer.

Suhail Yousuf, Mengjie Qiu, Lena Voith von Voithenberg, Johannes Hulkkonen, Igor Macinkovic, Axel R Schulz, Domenic Hartmann, Florian Mueller, Margarete Mijatovic, David Ibberson, Karam T AlHalabi, Jenny Hetzer, Simon Anders, Bernhard Brüne, Henrik E Mei, Charles D Imbusch, Benedikt Brors, Mathias Heikenwälder, Matthias M Gaida, Markus W Büchler, Andreas Weigert, Thilo Hackert, Susanne Roth.

   BACKGROUND & AIMS: As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially-resolved multimodal single cell approach.
METHODS: We applied single cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry and mass cytometry to profile the immune compartment in treatment naive PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures, and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma (LUAD) on single-cell level.
RESULTS: We provide a spatially-resolved fine map of the immune landscape in PDAC. We substantiate the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlight immune subsets with potentially underappreciated roles in PDAC, that diverge from immune populations within adjacent normal areas, particularly CD4 T cell subsets and NKT cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and LUAD revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition.
CONCLUSION: Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and LUAD, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.

Keywords:  lung cancer; pancreatic cancer; single cell multi-omics; tumor immunology

DOI:  https://doi.org/10.1053/j.gastro.2023.05.036
FEBS Lett. 2023 Jun 01.

Membrane association of the ATG8 conjugation machinery emerges as a key regulatory feature for autophagosome biogenesis.

Sharon A Tooze, Wenxin Zhang, Gianmarco Lazzeri, Deepanshi Gahlot, Lipi Thukral, Roberto Covino, Taki Nishimura.

  Autophagy is a highly conserved intracellular pathway which is essential for survival in all eukaryotes. In healthy cells, autophagy is used to remove damaged intracellular components, which can be as simple as unfolded proteins or as complex as whole mitochondria. Once the damaged component is captured, the autophagosome engulfs it and closes, isolating the content from the cytoplasm. The autophagosome then fuses with the late endosome and/or lysosome to deliver its content to the lysosome for degradation. Formation of the autophagosome, sequestration or capture of content, and closure all require the ATG proteins, which constitute the essential core autophagy protein machinery. This brief "nutshell" will highlight recent data revealing the importance of small membrane associated domains in the ATG proteins. In particular, recent findings from two parallel studies reveal the unexpected key role of α-helical structures in the ATG8 conjugation machinery and ATG8s. These studies illustrate how unique membrane association modules can control the formation of autophagosomes.

Keywords:  ATG3; ATG8 lipidation; Amphipathic α-helix; Autophagy; MD simulation; autophagosome size; cis-membrane association; membrane expansion

DOI:  https://doi.org/10.1002/1873-3468.14676
Nature. 2023 May 31.

Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

Dongsung Kim, Lorenz Herdeis, Dorothea Rudolph, Yulei Zhao, Jark Böttcher, Alberto Vides, Carlos I Ayala-Santos, Yasin Pourfarjam, Antonio Cuevas-Navarro, Jenny Y Xue, Andreas Mantoulidis, Joachim Bröker, Tobias Wunberg, Otmar Schaaf, Johannes Popow, Bernhard Wolkerstorfer, Katrin Gabriele Kropatsch, Rui Qu, Elisa de Stanchina, Ben Sang, Chuanchuan Li, Darryl B McConnell, Norbert Kraut, Piro Lito.

KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients1-7. Whether inactive-state selective inhibition can be used to therapeutically target non-G12C KRAS mutants remains under investigation. Here we report the discovery and characterization of a non-covalent inhibitor that binds preferentially and with high affinity to the inactive state of KRAS while sparing NRAS and HRAS. Although limited to only a few amino acids, the evolutionary divergence in the GTPase domain of RAS isoforms was sufficient to impart orthosteric and allosteric constraints for KRAS selectivity. The inhibitor blocked nucleotide exchange to prevent the activation of wild-type KRAS and a broad range of KRAS mutants, including G12A/C/D/F/V/S, G13C/D, V14I, L19F, Q22K, D33E, Q61H, K117N and A146V/T. Inhibition of downstream signalling and proliferation was restricted to cancer cells harbouring mutant KRAS, and drug treatment suppressed KRAS mutant tumour growth in mice, without having a detrimental effect on animal weight. Our study suggests that most KRAS oncoproteins cycle between an active state and an inactive state in cancer cells and are dependent on nucleotide exchange for activation. Pan-KRAS inhibitors, such as the one described here, have broad therapeutic implications and merit clinical investigation in patients with KRAS-driven cancers.

DOI: https://doi.org/10.1038/s41586-023-06123-3
Cell Rep. 2023 May 26. pii: S2211-1247(23)00573-9. [Epub ahead of print]42(6): 112562

ALDH1L2 regulation of formate, formyl-methionine, and ROS controls cancer cell migration and metastasis.

Marc Hennequart, Steven E Pilley, Christiaan F Labuschagne, Jack Coomes, Loic Mervant, Paul C Driscoll, Nathalie M Legrave, Younghwan Lee, Peter Kreuzaler, Benedict Macintyre, Yulia Panina, Julianna Blagih, David Stevenson, Douglas Strathdee, Deborah Schneider-Luftman, Eva Grönroos, Eric C Cheung, Mariia Yuneva, Charles Swanton, Karen H Vousden.

  Mitochondrial 10-formyltetrahydrofolate (10-formyl-THF) is utilized by three mitochondrial enzymes to produce formate for nucleotide synthesis, NADPH for antioxidant defense, and formyl-methionine (fMet) to initiate mitochondrial mRNA translation. One of these enzymes-aldehyde dehydrogenase 1 family member 2 (ALDH1L2)-produces NADPH by catabolizing 10-formyl-THF into CO2 and THF. Using breast cancer cell lines, we show that reduction of ALDH1L2 expression increases ROS levels and the production of both formate and fMet. Both depletion of ALDH1L2 and direct exposure to formate result in enhanced cancer cell migration that is dependent on the expression of the formyl-peptide receptor (FPR). In various tumor models, increased ALDH1L2 expression lowers formate and fMet accumulation and limits metastatic capacity, while human breast cancer samples show a consistent reduction of ALDH1L2 expression in metastases. Together, our data suggest that loss of ALDH1L2 can support metastatic progression by promoting formate and fMet production, resulting in enhanced FPR-dependent signaling.

Keywords:  ALDH1L2; CP: Cancer; CP: Metabolism; ROS; breast cancer; formate; formyl-methionine; metastasis; one-carbon metabolism; serine

DOI:  https://doi.org/10.1016/j.celrep.2023.112562
J Cell Biochem. 2023 Jun 01.

Immune modulation through secretory autophagy.

Andreas Weigert, Lina Herhaus.

  Autophagy is a central mechanism of cellular homeostasis through the degradation of a wide range of cellular constituents. However, recent evidence suggests that autophagy actively provides information to neighboring cells via a process called secretory autophagy. Secretory autophagy couples the autophagy machinery to the secretion of cellular content via extracellular vesicles (EVs). EVs carry a variety of cargo, that reflect the pathophysiological state of the originating cells and have the potential to change the functional profile of recipient cells, to modulate cell biology. The immune system has evolved to maintain local and systemic homeostasis. It is able to sense a wide array of molecules signaling disturbed homeostasis, including EVs and their content. In this review, we explore the emerging concept of secretory autophagy as a means to communicate cellular, and in total tissue pathophysiological states to the immune system to initiate the restoration of tissue homeostasis. Understanding how autophagy mediates the secretion of immunogenic factors may hold great potential for therapeutic intervention.

Keywords:  autophagy; cancer; extracellular vesicles; immunity; infection; inflammation; secretion; secretory autophagy

DOI:  https://doi.org/10.1002/jcb.30427
Mol Cell. 2023 Jun 01. pii: S1097-2765(23)00368-4. [Epub ahead of print]83(11): 1765-1766

An unexpected pathway to polyamines in pancreatic cancer.

Dominik Awad, Costas A Lyssiotis.

In most adult tissues, arginine is the precursor to polyamines, poly-cationic metabolites that interact with negatively charged biomolecules like DNA. Lee et al.1 discovered that pancreatic cancers synthesize polyamines from glutamine, illuminating a new pathway and underscoring their metabolic flexibility.

DOI: https://doi.org/10.1016/j.molcel.2023.05.014
Trends Mol Med. 2023 May 10. pii: S1471-4914(23)00074-6. [Epub ahead of print]

Dietary interventions and precision nutrition in cancer therapy.

Carlos Martínez-Garay, Nabil Djouder.

  In recent years dietary interventions have become a promising tool in cancer treatment and have demonstrated a powerful ability to alter metabolism and tumor growth, development, and therapeutic response. However, because the mechanisms underlying dietary therapeutics are poorly understood, they are frequently ignored as a potential line of treatment for cancer. We discuss the proposed mechanisms behind the anticancer effects of various diets and their development for clinical use. This review aims to provide researchers and clinicians in the field of oncology with a complete overview of the contemporary landscape of nutritional interventions and precision nutrition as cancer therapeutics, and offers a perspective on the steps necessary to establish nutritional interventions as a standard line of treatment.

Keywords:  caloric restriction; cancer metabolism; dietary interventions; fasting; fasting-mimicking diet; ketogenic diet; precision nutrition; time-restricted feeding

DOI:  https://doi.org/10.1016/j.molmed.2023.04.004
Cancer Cell. 2023 May 26. pii: S1535-6108(23)00172-1. [Epub ahead of print]

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.

Scott Haston, Estela Gonzalez-Gualda, Samir Morsli, Jianfeng Ge, Virinder Reen, Alexander Calderwood, Ilias Moutsopoulos, Leonidas Panousopoulos, Polina Deletic, Gabriela Carreno, Romain Guiho, Saba Manshaei, Jose Mario Gonzalez-Meljem, Hui Yuan Lim, Daniel J Simpson, Jodie Birch, Husayn A Pallikonda, Tamir Chandra, David Macias, Gary J Doherty, Doris M Rassl, Robert C Rintoul, Massimo Signore, Irina Mohorianu, Arne N Akbar, Jesús Gil, Daniel Muñoz-Espín, Juan Pedro Martinez-Barbera.

  The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.

Keywords:  ABT-737; NSCLC; aging; cancer; endothelial cells; immunosuppression; macrophages; p16INK4a; senescence; senolytic

DOI:  https://doi.org/10.1016/j.ccell.2023.05.004
Nat Med. 2023 Jun 02.

Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results.

Priscilla K Brastianos, Albert E Kim, Anita Giobbie-Hurder, Eudocia Q Lee, Nancy U Lin, Beth Overmoyer, Patrick Y Wen, Lakshmi Nayak, Justine V Cohen, Jorg Dietrich, April Eichler, Rebecca S Heist, Ian Krop, Donald Lawrence, Jennifer Ligibel, Sara Tolaney, Erica Mayer, Eric Winer, Brittany Bent, Magali A de Sauvage, Nazanin Ijad, Juliana M Larson, Braxton Marion, Sally Nason, Naina Murthy, Sherry Ratcliff, Elizabeth J Summers, Maura Mahar, Helen A Shih, Kevin Oh, Daniel P Cahill, Elizabeth R Gerstner, Ryan J Sullivan.

Brain metastases (BMs) are an emerging challenge in oncology due to increasing incidence and limited treatments. Here, we present results of a single-arm, open-label, phase 2 trial evaluating intracranial efficacy of pembrolizumab, a programmed cell death protein 1 inhibitor, in 9 patients with untreated BMs (cohort A) and 48 patients with recurrent and progressive BMs (cohort B) across different histologies. The primary endpoint was the proportion of patients achieving intracranial benefit, defined by complete response, partial response or stable disease. The primary endpoint was met with an intracranial benefit rate of 42.1% (90% confidence interval (CI): 31-54%). The median overall survival, a secondary endpoint, was 8.0 months (90% CI: 5.5-8.7 months) across both cohorts, 6.5 months (90% CI: 4.5-18.7 months) for cohort A and 8.1 months (90% CI: 5.3-9.6 months) for cohort B. Seven patients (12.3%), encompassing breast, melanoma and sarcoma histologies, had overall survival greater than 2 years. Thirty patients (52%; 90% CI: 41-64%) had one or more grade-3 or higher adverse events that were at least possibly treatment related. Two patients had grade-4 adverse events (cerebral edema) that were deemed at least possibly treatment related. These results suggest that programmed cell death protein 1 blockade may benefit a select group of patients with BMs, and support further studies to identify biomarkers and mechanisms of resistance. ClinicalTrials.gov identifier: NCT02886585.

DOI: https://doi.org/10.1038/s41591-023-02392-7
Proc Natl Acad Sci U S A. 2023 Jun 06. 120(23): e2217332120

Succinyl-CoA ligase ADP-forming subunit beta promotes stress granule assembly to regulate redox and drive cancer metastasis.

Austin C Boese, JiHoon Kang, Jung Seok Hwang, Jaehyun Kim, Kiyoung Eun, Courteney M Malin, Kelly R Magliocca, Chaoyun Pan, Lingtao Jin, Sumin Kang.

  Although recent studies demonstrate active mitochondrial metabolism in cancers, the precise mechanisms through which mitochondrial factors contribute to cancer metastasis remain elusive. Through a customized mitochondrion RNAi screen, we identified succinyl-CoA ligase ADP-forming subunit beta (SUCLA2) as a critical anoikis resistance and metastasis driver in human cancers. Mechanistically, SUCLA2, but not the alpha subunit of its enzyme complex, relocates from mitochondria to the cytosol upon cell detachment where SUCLA2 then binds to and promotes the formation of stress granules. SUCLA2-mediated stress granules facilitate the protein translation of antioxidant enzymes including catalase, which mitigates oxidative stress and renders cancer cells resistant to anoikis. We provide clinical evidence that SUCLA2 expression correlates with catalase levels as well as metastatic potential in lung and breast cancer patients. These findings not only implicate SUCLA2 as an anticancer target, but also provide insight into a unique, noncanonical function of SUCLA2 that cancer cells co-opt to metastasize.

Keywords:  mitochondrial metabolism; redox homeostasis; stress granule; succinyl-CoA ligase; tumor metastasis

DOI:  https://doi.org/10.1073/pnas.2217332120
Gastroenterology. 2023 May 30. pii: S0016-5085(23)00809-0. [Epub ahead of print]

TGFβ blockade in pancreatic cancer enhances sensitivity to combination chemotherapy.

Li Qiang, Megan T Hoffman, Lestat R Ali, Jaime I Castillo, Lauren Kageler, Ayantu Temesgen, Patrick Lenehan, S Jennifer Wang, Elisa Bello, Victoire Cardot-Ruffino, Giselle A Uribe, Annan Yang, Michael Dougan, Andrew J Aguirre, Srivatsan Raghavan, Marc Pelletier, Viviana Cremasco, Stephanie K Dougan.

   BACKGROUND AND AIMS: TGFβ plays pleiotropic roles in pancreatic cancer including promoting metastasis, attenuating CD8 T cell activation, and enhancing myofibroblast differentiation and deposition of extracellular matrix. However, single-agent TGFβ inhibition has shown limited efficacy against pancreatic cancer in mice or humans.
METHODS: We evaluated the TGFβ blocking antibody NIS793 in combination with either gemcitabine/n(ab)-paclitaxel or FOLFIRINOX chemotherapy in orthotopic pancreatic cancer models. Single-cell RNA-seq and immunofluorescence were used to evaluate changes in tumor cell state and the tumor microenvironment.
RESULTS: Blockade of TGFβ with chemotherapy reduced tumor burden in poorly immunogenic pancreatic cancer, without affecting the metastatic rate of cancer cells. Efficacy of combination therapy was not dependent on CD8 T cells, as response to TGFβ blockade was preserved in CD8-depleted or RAG2-/- mice. TGFβ blockade decreased total αSMA+ fibroblasts but had minimal effect on fibroblast heterogeneity. Bulk RNA-seq on tumor cells sorted ex vivo revealed that tumor cells treated with TGFβ blockade adopted a classical lineage consistent with enhanced chemosensitivity, and immunofluorescence for cleaved caspase 3 confirmed that TGFβ blockade increased chemotherapy-induced cell death in vivo.
CONCLUSIONS: TGFβ regulates pancreatic cancer cell plasticity between classical and basal cell states. TGFβ blockade in orthotropic models of pancreatic cancer enhances sensitivity to chemotherapy by promoting a classical malignant cell state. This study provides scientific rationale for evaluation of NIS793 with either FOLFIRINOX or gemcitabine/n(ab)paclitaxel chemotherapy backbone in the clinical setting and supports the concept of manipulating cancer cell plasticity to increase the efficacy of combination therapy regimens.

Keywords:  TGFβ; chemotherapy; immunotherapy; pancreatic cancer; tumor microenvironment

DOI:  https://doi.org/10.1053/j.gastro.2023.05.038
Nat Rev Clin Oncol. 2023 Jun 02.

Circulating tumour cells for early detection of clinically relevant cancer.

Rachel Lawrence, Melissa Watters, Caitlin R Davies, Klaus Pantel, Yong-Jie Lu.

Given that cancer mortality is usually a result of late diagnosis, efforts in the field of early detection are paramount to reducing cancer-related deaths and improving patient outcomes. Increasing evidence indicates that metastasis is an early event in patients with aggressive cancers, often occurring even before primary lesions are clinically detectable. Metastases are usually formed from cancer cells that spread to distant non-malignant tissues via the blood circulation, termed circulating tumour cells (CTCs). CTCs have been detected in patients with early stage cancers and, owing to their association with metastasis, might indicate the presence of aggressive disease, thus providing a possible means to expedite diagnosis and treatment initiation for such patients while avoiding overdiagnosis and overtreatment of those with slow-growing, indolent tumours. The utility of CTCs as an early diagnostic tool has been investigated, although further improvements in the efficiency of CTC detection are required. In this Perspective, we discuss the clinical significance of early haematogenous dissemination of cancer cells, the potential of CTCs to facilitate early detection of clinically relevant cancers, and the technological advances that might improve CTC capture and, thus, diagnostic performance in this setting.

DOI: https://doi.org/10.1038/s41571-023-00781-y
Clin Cancer Res. 2023 Jun 02. pii: CCR-22-3724. [Epub ahead of print]

Comparative Genomic Analysis of Pancreatic Acinar Cell Carcinoma (PACC) and Pancreatic Ductal Adenocarcinoma (PDAC)Unveils New Actionable Genomic Aberrations in PACC.

Vaia Florou, Andrew Elliott, Matthew H Bailey, David Stone, Kajsa Affolter, Heloisa P Soares, Chris Nevala-Plagemann, Courtney Scaife, Phillip Walker, W Michael Korn, Emil Lou, Rachna T Shroff, Peter J Hosein, Ignacio Garrido-Laguna.

PURPOSE: Pure pancreatic acinar cell carcinomas (PACC) are rare malignancies with no established treatment. PACC demonstrates significant genetic intertumoral heterogeneity with multiple pathways involved, suggesting using targeted cancer therapeutics to treat this disease. We aggregated one of the largest datasets of pure PACC to examine the genomic variability and explore patient-specific therapeutic targets.
EXPERIMENTAL DESIGN: PACC specimens (n=51) underwent next-generation sequencing (NGS) of DNA (n=29) or whole exome [n=22]) and RNA (whole transcriptome, n=29) at a commercial laboratory. We performed comparative analyses of a genomic cohort of pancreatic ductal adenocarcinomas (PDAC, n=4205). In parallel, we conducted a retrospective review patients with PACC treated at Huntsman Cancer Institute (HCI).
RESULTS: The real-world dataset included samples from 51 patients with PACC. We found key molecular differences between pure PACC and PDAC, highlighting the unique characteristics of pure PACC. Major differences in PACC include lower MAPK signaling and less stromal cell abundance compared to PDAC. Pure PACC showed genomic loss-of-heterozygosity to largely coincide with mutations in BRCA1, BRCA2, and PALB2. Of the seven patients treated at HCI, one had a tumor that harbored a BRAF-V600E mutation. Leveraging precision oncology, this patient is being treated with encorafenib plus binimetinib, achieving an exceptionally durable and ongoing complete response of more than three years.
CONCLUSIONS: There are major differences between PACC and PDAC, including downregulation of the MAPK signaling pathway, and less stromal cell abundance. In addition, genomic characterization of pure PACC revealed frequent targetable alterations, which can guide patient treatment.

DOI: https://doi.org/10.1158/1078-0432.CCR-22-3724
Cell Stem Cell. 2023 Jun 01. pii: S1934-5909(23)00171-6. [Epub ahead of print]30(6): 885-903.e10

Transcriptional space-time mapping identifies concerted immune and stromal cell patterns and gene programs in wound healing and cancer.

Kenneth H Hu, Nicholas F Kuhn, Tristan Courau, Jessica Tsui, Bushra Samad, Patrick Ha, Johannes R Kratz, Alexis J Combes, Matthew F Krummel.

  Tissue repair responses in metazoans are highly coordinated by different cell types over space and time. However, comprehensive single-cell-based characterization covering this coordination is lacking. Here, we captured transcriptional states of single cells over space and time during skin wound closure, revealing choreographed gene-expression profiles. We identified shared space-time patterns of cellular and gene program enrichment, which we call multicellular "movements" spanning multiple cell types. We validated some of the discovered space-time movements using large-volume imaging of cleared wounds and demonstrated the value of this analysis to predict "sender" and "receiver" gene programs in macrophages and fibroblasts. Finally, we tested the hypothesis that tumors are like "wounds that never heal" and found conserved wound healing movements in mouse melanoma and colorectal tumor models, as well as human tumor samples, revealing fundamental multicellular units of tissue biology for integrative studies.

Keywords:  cell-cell crosstalk; fibroblasts; gene programs; immunology; macrophage; skin; systems biology; tumor microenvironment; wound healing

DOI:  https://doi.org/10.1016/j.stem.2023.05.001
Nat Rev Gastroenterol Hepatol. 2023 Jun 02.

AI predicts pancreatic cancer risk.

Ian Fyfe.

DOI: https://doi.org/10.1038/s41575-023-00802-2
iScience. 2023 Jun 16. 26(6): 106820

Inflammatory and alternatively activated macrophages independently induce metaplasia but cooperatively drive pancreatic precancerous lesion growth.

Geou-Yarh Liou, Alicia K Fleming Martinez, Heike R Döppler, Ligia I Bastea, Peter Storz.

  The innate immune system has a key role in pancreatic cancer initiation, but the specific contribution of different macrophage populations is still ill-defined. While inflammatory (M1) macrophages have been shown to drive acinar-to-ductal metaplasia (ADM), a cancer initiating event, alternatively activated (M2) macrophages have been attributed to lesion growth and fibrosis. Here, we determined cytokines and chemokines secreted by both macrophage subtypes. Then, we analyzed their role in ADM initiation and lesion growth, finding that while M1 secrete TNF, CCL5, and IL-6 to drive ADM, M2 induce this dedifferentiation process via CCL2, but the effects are not additive. This is because CCL2 induces ADM by generating ROS and upregulating EGFR signaling, thus using the same mechanism as cytokines from inflammatory macrophages. Therefore, while effects on ADM are not additive between macrophage polarization types, both act synergistically on the growth of low-grade lesions by activating different MAPK pathways.

Keywords:  Cancer; Cell biology; Immunology; Molecular biology

DOI:  https://doi.org/10.1016/j.isci.2023.106820
Nat Commun. 2023 Jun 02. 14(1): 3192

Lipid droplets are a metabolic vulnerability in melanoma.

Dianne Lumaquin-Yin, Emily Montal, Eleanor Johns, Arianna Baggiolini, Ting-Hsiang Huang, Yilun Ma, Charlotte LaPlante, Shruthy Suresh, Lorenz Studer, Richard M White.

Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.

DOI: https://doi.org/10.1038/s41467-023-38831-9
Cancer Cell. 2023 May 24. pii: S1535-6108(23)00171-X. [Epub ahead of print]

Senescent alveolar macrophages promote early-stage lung tumorigenesis.

Luis I Prieto, Ines Sturmlechner, Sara I Graves, Cheng Zhang, Nick P Goplen, Eunhee S Yi, Jie Sun, Hu Li, Darren J Baker.

  Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.

Keywords:  aging; alveolar macrophages; cellular senescence; cytotoxic T cells; senolytic

DOI:  https://doi.org/10.1016/j.ccell.2023.05.006
Trends Cancer. 2023 May 27. pii: S2405-8033(23)00084-5. [Epub ahead of print]

Clinical and translational relevance of intratumor heterogeneity.

Marie-Anne Goyette, Marla Lipsyc-Sharf, Kornelia Polyak.

  Intratumor heterogeneity (ITH) is a driver of tumor evolution and a main cause of therapeutic resistance. Despite its importance, measures of ITH are still not incorporated into clinical practice. Consequently, standard treatment is frequently ineffective for patients with heterogeneous tumors as changes to treatment regimens are made only after recurrence and disease progression. More effective combination therapies require a mechanistic understanding of ITH and ways to assess it in clinical samples. The growth of technologies enabling the spatially intact analysis of tumors at the single-cell level and the development of sophisticated preclinical models give us hope that ITH will not simply be used as a predictor of a poor outcome but will guide treatment decisions from diagnosis through treatment.

Keywords:  clonal interaction; intratumor heterogeneity; single-cell technologies; treatment resistance; tumor plasticity

DOI:  https://doi.org/10.1016/j.trecan.2023.05.001
Nature. 2023 May 31.

In situ tumour arrays reveal early environmental control of cancer immunity.

Guadalupe Ortiz-Muñoz, Markus Brown, Catherine B Carbone, Ximo Pechuan-Jorge, Vincent Rouilly, Henrik Lindberg, Alex T Ritter, Gautham Raghupathi, Qianbo Sun, Tess Nicotra, Shreya R Mantri, Angela Yang, Jonas Doerr, Deepti Nagarkar, Spyros Darmanis, Benjamin Haley, Sanjeev Mariathasan, Yulei Wang, Carlos Gomez-Roca, Carlos Eduardo de Andrea, David Spigel, Thomas Wu, Lelia Delamarre, Johannes Schöneberg, Zora Modrusan, Richard Price, Shannon J Turley, Ira Mellman, Christine Moussion.

The immune phenotype of a tumour is a key predictor of its response to immunotherapy1-4. Patients who respond to checkpoint blockade generally present with immune-inflamed5-7 tumours that are highly infiltrated by T cells. However, not all inflamed tumours respond to therapy, and even lower response rates occur among tumours that lack T cells (immune desert) or that spatially exclude T cells to the periphery of the tumour lesion (immune excluded)8. Despite the importance of these tumour immune phenotypes in patients, little is known about their development, heterogeneity or dynamics owing to the technical difficulty of tracking these features in situ. Here we introduce skin tumour array by microporation (STAMP)-a preclinical approach that combines high-throughput time-lapse imaging with next-generation sequencing of tumour arrays. Using STAMP, we followed the development of thousands of arrayed tumours in vivo to show that tumour immune phenotypes and outcomes vary between adjacent tumours and are controlled by local factors within the tumour microenvironment. Particularly, the recruitment of T cells by fibroblasts and monocytes into the tumour core was supportive of T cell cytotoxic activity and tumour rejection. Tumour immune phenotypes were dynamic over time and an early conversion to an immune-inflamed phenotype was predictive of spontaneous or therapy-induced tumour rejection. Thus, STAMP captures the dynamic relationships of the spatial, cellular and molecular components of tumour rejection and has the potential to translate therapeutic concepts into successful clinical strategies.

DOI: https://doi.org/10.1038/s41586-023-06132-2
Nat Med. 2023 May 29.

Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance.

Yanshuo Chu, Enyu Dai, Yating Li, Guangchun Han, Guangsheng Pei, Davis R Ingram, Krupa Thakkar, Jiang-Jiang Qin, Minghao Dang, Xiuning Le, Can Hu, Qing Deng, Ansam Sinjab, Pravesh Gupta, Ruiping Wang, Dapeng Hao, Fuduan Peng, Xinmiao Yan, Yunhe Liu, Shumei Song, Shaojun Zhang, John V Heymach, Alexandre Reuben, Yasir Y Elamin, Melissa P Pizzi, Yang Lu, Rossana Lazcano, Jian Hu, Mingyao Li, Michael Curran, Andrew Futreal, Anirban Maitra, Amir A Jazaeri, Jaffer A Ajani, Charles Swanton, Xiang-Dong Cheng, Hussein A Abbas, Maura Gillison, Krishna Bhat, Alexander J Lazar, Michael Green, Kevin Litchfield, Humam Kadara, Cassian Yee, Linghua Wang.

Tumor-infiltrating T cells offer a promising avenue for cancer treatment, yet their states remain to be fully characterized. Here we present a single-cell atlas of T cells from 308,048 transcriptomes across 16 cancer types, uncovering previously undescribed T cell states and heterogeneous subpopulations of follicular helper, regulatory and proliferative T cells. We identified a unique stress response state, TSTR, characterized by heat shock gene expression. TSTR cells are detectable in situ in the tumor microenvironment across various cancer types, mostly within lymphocyte aggregates or potential tertiary lymphoid structures in tumor beds or surrounding tumor edges. T cell states/compositions correlated with genomic, pathological and clinical features in 375 patients from 23 cohorts, including 171 patients who received immune checkpoint blockade therapy. We also found significantly upregulated heat shock gene expression in intratumoral CD4/CD8+ cells following immune checkpoint blockade treatment, particularly in nonresponsive tumors, suggesting a potential role of TSTR cells in immunotherapy resistance. Our well-annotated T cell reference maps, web portal and automatic alignment/annotation tool could provide valuable resources for T cell therapy optimization and biomarker discovery.

DOI: https://doi.org/10.1038/s41591-023-02371-y
Nature. 2023 May 31.

Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours.

Avishai Gavish, Michael Tyler, Alissa C Greenwald, Rouven Hoefflin, Dor Simkin, Roi Tschernichovsky, Noam Galili Darnell, Einav Somech, Chaya Barbolin, Tomer Antman, Daniel Kovarsky, Thomas Barrett, L Nicolas Gonzalez Castro, Debdatta Halder, Rony Chanoch-Myers, Julie Laffy, Michael Mints, Adi Wider, Rotem Tal, Avishay Spitzer, Toshiro Hara, Maria Raitses-Gurevich, Chani Stossel, Talia Golan, Amit Tirosh, Mario L Suvà, Sidharth V Puram, Itay Tirosh.

Each tumour contains diverse cellular states that underlie intratumour heterogeneity (ITH), a central challenge of cancer therapeutics1. Dozens of recent studies have begun to describe ITH by single-cell RNA sequencing, but each study typically profiled only a small number of tumours and provided a narrow view of transcriptional ITH2. Here we curate, annotate and integrate the data from 77 different studies to reveal the patterns of transcriptional ITH across 1,163 tumour samples covering 24 tumour types. Among the malignant cells, we identify 41 consensus meta-programs, each consisting of dozens of genes that are coordinately upregulated in subpopulations of cells within many tumours. The meta-programs cover diverse cellular processes including both generic (for example, cell cycle and stress) and lineage-specific patterns that we map into 11 hallmarks of transcriptional ITH. Most meta-programs of carcinoma cells are similar to those identified in non-malignant epithelial cells, suggesting that a large fraction of malignant ITH programs are variable even before oncogenesis, reflecting the biology of their cell of origin. We further extended the meta-program analysis to six common non-malignant cell types and utilize these to map cell-cell interactions within the tumour microenvironment. In summary, we have assembled a comprehensive pan-cancer single-cell RNA-sequencing dataset, which is available through the Curated Cancer Cell Atlas website, and leveraged this dataset to carry out a systematic characterization of transcriptional ITH.

DOI: https://doi.org/10.1038/s41586-023-06130-4
Cancer Discov. 2023 May 31. pii: CD-22-0874. [Epub ahead of print]

FH variant pathogenicity promotes purine salvage pathway dependence in kidney cancer.

Blake R Wilde, Nishma Chakraborty, Nedas Matulionis, Stephanie Hernandez, Daiki Ueno, Michayla E Gee, Edward D Esplin, Karen Ouyang, Keith Nykamp, Brian Shuch, Heather R Christofk.

Fumarate accumulation due to loss of fumarate hydratase (FH) drives cellular transformation. Germline FH alterations lead to hereditary leiomyomatosis and renal cell cancer (HLRCC) where patients are predisposed to an aggressive form of kidney cancer. There is an unmet need to classify FH variants by cancer-associated risk. We quantified catalytic efficiencies of 74 variants of uncertain significance. Over half were enzymatically inactive which is strong evidence of pathogenicity. We next generated a panel of HLRCC cell lines expressing FH variants with a range of catalytic activities, then correlated fumarate levels with metabolic features. We found that fumarate accumulation blocks de novo purine biosynthesis, rendering FH-deficient cells reliant on purine salvage for proliferation. Genetic or pharmacologic inhibition of the purine salvage pathway reduced HLRCC tumor growth in vivo. These findings suggest pathogenicity of patient-associated FH variants and reveal purine salvage as a targetable vulnerability in FH-deficient tumors.

DOI: https://doi.org/10.1158/2159-8290.CD-22-0874